PROJECT SUMMARY Despite successful advancements in antiretroviral therapy (ART), a significant proportion of individuals worldwide are unaware of their HIV-infection. Detecting persons with acute HIV infection is crucial since viral replication and shedding occur in this stage before detectable HIV antibodies appear. Persons with acute HIV infection can contribute substantially to HIV transmission. Viral rebound in individuals on ART can occur due to drug resistance and ART non-adherence. Early detection of viral rebound can significantly affect the disease management by allowing treatment intervention and preventing clinical progression. Furthermore, treatment interruption has become a vital tool in the assessment of new therapies for achieving ART-free HIV remission. However, these trials entail risks to the participants, which could be mitigated with more frequent self-directed viral load monitoring. Despite the sensitivity and specificity, nucleic acid testing (NAT) cannot be implemented at the point-of-care (POC) due to prohibitive cost and demand for skilled operators. Current antibody-based POC technologies, such as dipsticks and enzyme-linked immunoassays (ELISA), are not effective to detect either ART failure or acute HIV. It has been shown that p24 antigen results for a given viral RNA load may vary, which makes p24 assays less trustworthy. In addition, p24 assays may provide false-negative results due to the presence of p24-specific antibodies in serum. Thus, there is an immediate need for an easy-to-use, portable, and inexpensive diagnostic tool for detecting acute HIV during the first two weeks after infection and viral rebound in individuals on ART after treatment discontinuation or drug resistance. Viral load testing is the most accurate and preferred approach for ART monitoring and acute HIV detection, and is highly recommended by WHO guidelines as an important tool for HIV management and treatment monitoring. To address this significant clinical barrier, we propose to develop a low-cost, rapid, and sensitive optical system for rapid (<30 min) detection of acute HIV (first two weeks after infection) and viral rebound (after terminating ART or due to drug resistance) using fingerprick volume (<100 L) of whole blood placed on an inexpensive, disposable, and mass-producible microfluidic device. The advances in microtechnologies and the surge in consumer electronics have paved a solid foundation for developing mobile health (mhealth) technologies with the potential to transform the current paradigm in global health. Smartphones can be seamlessly integrated with hardware, software, and microfluidics to develop a true POC diagnostic device to address clinical gaps in HIV management.